The introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors has provided physicians with greater options for the management of patients with diabetes, and trials continue to investigate how these agents compare with existing anti-diabetic therapies and how they might best be incorporated into treatment regimes. At a MSD-sponsored symposium during the 47th Annual Meeting of the European Association for the Study of Diabetes (EASD) held in Lisbon, Portugal last year, experts discussed the findings of such trials and more.

Sitagliptin effective, alone and in combination

Sitagliptin effectively lowers HbA1c as monotherapy or in combination with other oral agents and insulin, with good body weight profile and minimal hypoglycemia, says Professor Philip Home, professor of diabetes medicine, Newcastle University, UK.

Sitagliptin (Januvia®, Merck Sharp & Dohme), a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be non-inferior to metformin in lowering HbA1c in people with type 2 diabetes mellitus (T2DM), but with fewer gastrointestinal-related adverse effects such as diarrhea and nausea, said Home. In the study, patients with HbA1c of 6.5 to 9.0 % units and who were not on any oral glucose-lowering medication in the last 4 months were randomized to metformin, which was titrated over 5 weeks to 1000 mg twice daily, or sitagliptin 100 mg once daily. From a mean baseline HbA1c of 7.2 % units, change from baseline was -0.43 % units with sitagliptin (n=455) and -0.57 % units with metformin (n=439). The between-group difference (95% CI) was 0.14 % units (0.06, 0.21), thus confirming non-inferiority. (Figure 1) [Diabetes Obes Metab 2010;12:252-61]

In comparison with sulfonylureas ie, glipizide and glimepiride, he noted that sitagliptin showed similar HbA1c reduction, but with significantly lower incidence of hypoglycemia (P<0.001). From a mean baseline of 7.5 % units, HbA1c changes were -0.67 % units at week 52 in both the sitagliptin and glipizide groups, confirming non-inferiority. When sitagliptin was compared with glimepiride, the difference in HbA1c changes also confirmed non-inferiority. Furthermore, sitagliptin was weight neutral, while the sulfonylureas caused weight gain. [Diabetes Obes Metab 2007;9:194-205, Int J Clin Pract 2010;64:562-76, Diabetes Obes Metab 2011;13:160-8]

However, he added, the GLP-1 receptor agonist therapies, liraglutide and exenatide once weekly, reduced HbA1c significantly more than sitagliptin (P<0.0001 for both). [Lancet 2010;375:1447-56, 376:431-9]

The fixed dose combination of sitagliptin 50 mg and metformin 1000 mg (Janumet®, MSD) significantly reduced HbA1c compared with metformin monotherapy. At week 18, the mean change from baseline HbA1c was -2.4 % units for sitagliptin/metformin and -1.8 % units for metformin monotherapy (P<0.001). (Figure 2) About 9 percent of people on sitagliptin/metformin received additional glucose-lowering therapy compared with about 17 percent in the metformin monotherapy group (P<0.001). [Diabetes Obes Metab 2011;13:644-52, 841-9] The combination of sitagliptin and pioglitazone also significantly reduced HbA1c compared with pioglitazone monotherapy, with a mean reduction from baseline HbA1c of -2.4 % units compared with -1.5 % units (P<0.001). [Int J Clin Pract 2011;65:154-64]

When added to insulin, sitagliptin significantly reduced HbA1c, but a higher incidence of hypoglycemia was noted. In this study, patients inadequately controlled on long-acting, intermediate-acting or premixed insulin with HbA1c of 7.5 to 11.0 % units were randomized to the addition of sitagliptin 100 mg once daily or placebo for 24 weeks. At 24 weeks, the addition of sitagliptin significantly reduced HbA1c by 0.6 % units compared with placebo (0.0 % units) (P<0.001). Although a higher incidence of hypoglycemia was reported with sitagliptin (16 percent) versus placebo (8 percent), the number of hypoglycemic events meeting the criteria for severity was low with sitagliptin (n=2). [Diabetes Obes Metab 2010;12:167-77]

A pooled safety analysis of 19 double-blind randomized studies of patients with T2DM comparing sitagliptin and non-sitagliptin groups found that treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events. [BMC Endocr Disord 2010;10:7] “Furthermore, there is a hope in the future that we will have as an indication positive vascular protection beyond glucose lowering itself,” concluded Home.

Working at islet level to re-activate beta cells

Speaking on incretin therapies, Professor Juris J. Meier, of the department of medicine I, St. Josef-Hospital, Ruhr-University Bochum, Germany, said GLP-1 has different effects at the islet level. Firstly, GLP-1 can turn inactive beta cells into active glucose-sensitive beta cells and increases beta cell mass by inhibiting beta cell apoptosis in humans. GLP-1 also increases islet insulin content – insulin is stimulated by GLP-1 only when glucose levels exceed 70 mg/dL, while glucagon secretion is suppressed when fasting glucose levels are 80 mg/dL to 100 mg/dL, said Meier. [J Clin Endocrinol Metab 2002;87:1239-46]

GLP-1 also stimulates the release of somatostatin from delta cells simultaneously. Somatostatin then acts on alpha cells to lower glucagon secretion in a glucose-dependent fashion. The combined effects of insulin and glucagon explain the reduction in hepatic glucose production and the amelioration in peripheral insulin action, he added. [Diabetes 2010;59:1765-70]

In patients with T2DM, there is an obvious reduction in beta cell mass, leading to an insufficient increase in insulin pulsatility. “This causes an insufficient suppression of glucagon, which ultimately causes an increase in hepatic glucose release and leads to development of hyperglycemia,” said Meier.

In contrast, insulin and glucagon are clearly secreted in a pulsatile fashion, with pulses occurring at approximately 5-minute intervals in non-diabetic individuals. Furthermore, there is an obvious inverse relationship between both hormones ie, when insulin levels rise there is a concomitant decline in glucagon levels and vice versa. This interrelationship between pulsatile insulin and glucagon secretion was validated and confirmed at a statistical level. The result of a cross correlation analysis performed on 13 non-diabetic individuals showed that there is, indeed, an inverse relationship. Interestingly, the same kind of analysis of patients with T2DM showed that this inverse association between insulin and glucagon secretion was completely lost, said Meier. [Diabetes 2011;60(8):2160-8]

Trials underway to confirm CV benefits

Focusing on the cardiovascular (CV) system, Dr. Mansoor Husain, director of the Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Canada, said GLP-1, GLP-1 receptor agonists and DPP-4 inhibitors also exert biological effects on the myocardium, endothelium and blood pressure of humans. [Circulation 2004;109:962-5, Circ Cardiovasc Imaging 2010;3:195-201, Am J Physiol Metab 2007;293:E1289-95, Diabetes Care 2010;33:1028-30, Am J Hypertens 2010;23:334-9, J Clin Pharmacol 2008;48:592-8, BMC Endocr Disord 2010;10:7] While these effects appear to be beneficial, clinical trials already underway are needed to evaluate the long-term outcomes of these drugs in diabetes.

The actions of GLP-1 are believed to depend on activation of an adenylate cyclase-associated G-protein-coupled receptor (GPCR), labeled GLP-1R, which has been shown to be expressed in the CV system. GLP-1 increases myocardial glucose uptake and left ventricular performance in dogs with pacing-induced dilated cardiomyopathy, and can directly protect the rat heart against ischemia/reperfusion injury. [Circulation 2004;110:955-61, Diabetes 2005;54:146-51, J Pharmacol Exp Ther 2006;317:1106-13] Also, GLP-1 and its metabolite vasodilate mesenteric arteries and increase coronary flow. [Circulation 2008;117:2340-50] These effects do not entirely depend on the known GLP-1 receptor.

Pre-treatment with the GLP-I receptor agonist liraglutide reduced cardiac rupture and infarct size, and increased survival. These effects were independent of weight loss. [Diabetes 2009;58:975-83]

With regard to DPP-4 inhibition, a study showed that diabetic mice on a DPP-4 inhibitor had increased survival over untreated controls following myocardial infarction (MI). Inhibition of DPP-4 in vivo was associated with activation of survival kinases in the heart and protection from ischemia/reperfusion injury. [Diabetes 2010;59:1063-73]

In humans, GLP-1 improved cardiac function in patients with acute MI and high risk of post-MI haeart failure after successful reperfusion. [Circulation 2004;109:962-5] Native GLP-1 improved endothelial function in non-diabetic as well as diabetic individuals. [Am J Physiol Endocrinol Metab 2007;293:E1289-95, 2004;287:E1209-15]

Exenatide improved endothelial dysfunction after a high-fat meal. [Diabetes Care 2010;33:1028-30] It also reduced systolic blood pressure in patients with T2DM. [Am J Hypertens 2010;23:334-9]

Sitagliptin improved left ventricular function response to dobutamine stress in patients with coronary artery disease. [Circ Cardiovasc Imaging 2010;3:195-201